Pharmacokinetic/pharmacodynamic data extrapolation models for improved pediatric efficacy and toxicity estimation, with application to secondary hyperparathyroidism.
Pharmacokinetic/pharmacodynamic data extrapolation models for improved pediatric efficacy and toxicity estimation, with application to secondary hyperparathyroidism.
复制标题
药代动力学/药效学数据外推模型，用于改善儿科疗效和毒性估计，并应用于继发性甲状旁腺功能亢进症。
DOI：
10.1002/pst.2043
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发表时间：
2020
影响因子：
1.5
通讯作者：
Carlin,BradleyP
中科院分区：
文献类型：
--
作者：
Basu,Cynthia;Ma,Xiaoye;Mo,May;Xia,HongAmy;Brundage,Richard;Al-Kofahi,Mahmoud;Carlin,BradleyP
在大多数药物开发环境中，监管审批过程伴随着广泛的研究，以了解药物的药代动力学（PK）和药效学（PD）特性。在本文中，我们试图利用丰富的PK/PD数据，为儿童药物开发过程中的成人信息借鉴提供信息。在儿科环境中，我们对实验招募的患者进行节俭是特别重要的。我们在cinacalcet治疗儿童和成人慢性肾病患者继发性甲状旁腺功能亢进症的临床试验中阐述了我们的方法，我们对甲状旁腺激素（疗效终点）和校正钙水平（安全性终点）进行了建模。我们使用种群PK/PD模型对cinacalcet数据进行定量评估成人和儿童之间的相似性，并将这些信息用于各种分层贝叶斯成人借用规则中，然后可以评估这些规则的统计特性。特别是，我们模拟了我们的方法的偏差和均方误差性能，在借用和不借用的情况下，为我们的方法的未来使用提供指导。
In most drug development settings, the regulatory approval process is accompanied by extensive studies performed to understand the drug's pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this article, we attempt to utilize the rich PK/PD data to inform the borrowing of information from adults during pediatric drug development. In pediatric settings, it is especially crucial that we are parsimonious with the patients recruited for experimentation. We illustrate our approaches in the context of clinical trials of cinacalcet for treating secondary hyperparathyroidism in pediatric and adult patients with chronic kidney disease, where we model both parathyroid hormone (efficacy endpoint) and corrected calcium levels (safety endpoint). We use population PK/PD modeling of the cinacalcet data to quantitatively assess the similarity between adults and children, and use this information in various hierarchical Bayesian adult borrowing rules whose statistical properties can then be evaluated. In particular, we simulate the bias and mean square error performance of our approaches in settings where borrowing is and is not warranted to inform guidelines for the future use of our methods.